tbuckley/cabot-search huggingface dataset:
Translating metagenomics into clinical practice for complex paediatric neurological presentations
Authors: Justin Penner, Jane Hassell, Julianne R Brown, Kshitij Mankad, Nathaniel Storey, Laura Atkinson, Nisha Ranganathan, Alexander Lennon, Jack C D Lee, Dimitrios Champsas, Angelika Kopec, Divya Shah, Cristina Venturini, Garth Dixon, Surjo De, James Hatcher, Kathryn Harris, Kristian Aquilina, Maaike A Kusters, Karyn Moshal, Delane Shingadia, Austen J J Worth, Giovanna Lucchini, Ashirwad Merve, Thomas S Jacques, Alasdair Bamford, Marios Kaliakatsos, Judith Breuer, Sofia Morfopoulou
Journal: Journal of Infection (2023)
Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms
Authors: Elodie Grockowiak, Claudia Korn, Justyna Rak, Veronika Lysenko, Adrien Hallou, Francesca M Panvini, Matthew Williams, Claire Fielding, Zijian Fang, Eman Khatib-Massalha, Andrés García-García, Juan Li, Reema A Khorshed, Sara González-Antón, E Joanna Baxter, Anjali Kusumbe, Bridget S Wilkins, Anna Green, Benjamin D Simons, Claire N Harrison, Anthony R Green, Cristina Lo Celso, Alexandre P A Theocharides, Simón Méndez-Ferrer
Journal: Nature Cancer (2023)

Abstract Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK–STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.
Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response
Authors: J N Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A Cassel, Christopher M Adams, Richard M Higashi, David A Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N Lane, Teresa W-M Fan, Ji Zhang, Ruoning Wang
Journal: Nature Metabolism (2023)

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8
IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells
Authors: Weiwei Wu, Tiongsun Chia, Jia Lu, Xue Li, Jian Guan, Yaning Li, Fenggen Fu, Shuaixiang Zhou, Ye Feng, Junjie Deng, Jia Zou, Jiya Sun, Ying Yao, Xiaomin Ling, Zhihai Wu, Ying Zhang, Jinling Xu, Feifei Wang, Xue Liang, Min Wu, Huisi Liu, Bingliang Chen, Kaijie He
Journal: Nature Cancer (2023)
iNOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway
Authors: Yongzheng Guo, Yuehua You, Fei-Fei Shang, Xiaowen Wang, Bi Huang, Boying Zhao, Dingyi Lv, Shenglan Yang, Ming Xie, Lingwen Kong, Dingyuan Du, Suxin Luo, Xin Tian, Yong Xia
Journal: Theranostics (2023)

Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension.Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation.However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown.Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC).iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts.Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function.Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout.Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA.In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function.Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts.Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload.iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.
TRPM2 protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction via modulating autophagy
Authors: Binfeng Yu, Lini Jin, Xi Yao, Yi Zhang, Gensheng Zhang, Fangqin Wang, Xinwan Su, Qiuyuan Fang, Liang Xiao, Yi Yang, Lin-Hua Jiang, Jianghua Chen, Wei Yang, Weiqiang Lin, Fei Han
Journal: Theranostics (2023)

Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity.Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis.Methods: Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and Trpm2-knockout mice and primary cells.RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity.Results: Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin.Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger.TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca 2+ influx and subsequent up-regulation of AKT-mTOR signaling.Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor.Conclusion: Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca 2+ -AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.
Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation
Authors: Wenqiang Xin, Yongli Pan, Wei Wei, Lars Tatenhorst, Irina Graf, Aurel Popa-Wagner, Stefan T Gerner, Sabine Huber, Ertugrul Kilic, Dirk M Hermann, Mathias Bähr, Hagen B Huttner, Thorsten R Doeppner
Journal: Theranostics (2023)

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation.Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury.Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow.Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury.For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established.Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury.Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice.Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery.Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further.In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs.Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes.Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release.
Tackling regulated cell death yields enhanced protection in lung grafts
Authors: Qian Chen, Xiangfeng Liu, Zhiheng Liu, Shujing Zhang, Lin Chen, Shiori Eguchi, Azeem Alam, Zhen Cahilog, Qizhe Sun, Lingzhi Wu, Enqiang Chang, Zhiping Wang, Jianteng Gu, Hailin Zhao, Daqing Ma
Journal: Theranostics (2023)

Background: Effective preservation strategies to ameliorate lung graft ischaemia injury are needed to rescue 'extended criteria' or 'marginal' lung grafts, and to improve recipient outcomes after transplantation. Methods: Lung grafts from male Lewis rats were extracted after 40 min of cardiocirculatory death, and healthy human lung tissues were collected from patients undergoing a lobectomy. Lung samples were then preserved in a 4°C preservation solution supplemented with 0.1 nM Dexmedetomidine (Dex, α2-adrenoceptor agonist) for 16 h. In vitro, human lung epithelial A549 cells were preserved in the 4°C preservation solution with 0.1 nM Dex for 24 h, then re-cultured in the cell culture medium at 37°C to mimic the clinical scenario of cold ischaemia and warm reperfusion. Lung tissues and cells were then analysed with various techniques including western blot, immunostaining and electron microscope, to determine injuries and the protection of Dex. Results: Prolonged warm ischaemia after cardiocirculatory death initiated Rip kinase-mediated necroptosis, which was exacerbated by cold storage insult and enhanced lung graft injury. Dex supplementation significantly reduced necroptosis through upregulating Nrf2 activation and reducing oxidative stress, thereby significantly improving lung graft morphology. Dex treatment also attenuated endoplasmic reticulum stress, stabilised lysosomes and promoted cell membrane resealing function, consequently reducing cell death and inflammatory activation after hypothermic hypoxia-reoxygenation in A549 cells. Conclusions: Inhibition of regulated cell death through Dex supplementation to the graft preservation solution improves allograft quality which may aid to expand the donor lung pool and enhance lung transplant outcomes per se.
Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer
Authors: Yu-Yuan Wu, Ya-Ling Hsu, Yung-Chi Huang, Yue-Chiu Su, Kuan-Li Wu, Chao-Yuan Chang, Chai-Tung Ong, Jia-Chen Lai, Tzu-Yen Shen, Tai-Huang Lee, Jen-Yu Hung, Ying-Ming Tsai
Journal: Theranostics (2023)

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete. Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression. Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1. Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.
Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis: Erratum
Authors: Meng Qi, Liqiang Zhang, Yang Ma, Yi Shuai, Liya Li, Kefu Luo, Wenjia Liu, Yan Jin
Journal: Theranostics (2023)

[This corrects the article DOI: 10.7150/thno.17949.].
Per- and Polyfluoroalkyl Substances (PFAS) and Lipid Trajectories in Women 45–56 Years of Age: The Study of Women’s Health Across the Nation
Authors: Habyeong Kang, Ning Ding, Carrie A. Karvonen-Gutierrez, Bhramar Mukherjee, Antonia M. Calafat, Sung Kyun Park
Journal: Environmental Health Perspectives (2023)

Background: Per- and polyfluoroalkyl substances (PFAS) are associated with less favorable blood lipid profiles in epidemiological studies. However, little is known about the potential role of PFAS in longitudinal changes in lipids among midlife women even though women become more susceptible to metabolic alterations during the menopausal transition. Objectives: To examine associations of serum PFAS concentrations with longitudinal trajectories of blood total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in midlife women undergoing menopausal transition. Methods: The sample included 1,130 women from the Study of Women's Health Across the Nation 45–56 y of age at baseline (1999–2000). We measured serum PFAS concentrations including linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), linear and branched perfluorooctanesulfonic acid (n-PFOS and Sm-PFOS, respectively), and perfluorohexanesulfonic acid (PFHxS) at baseline. We used k-means clustering to identify subgroups with different patterns of PFAS mixture. Blood lipids were measured annually or biannually through 2016 with an average follow-up of 14.8 y. We identified longitudinal trajectories of each lipid using latent class growth models. We used multinomial log-linear models adjusted for covariates to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of lipid trajectory classes by PFAS and their mixtures. Results: Three distinct trajectories (low, middle, high) of total, LDL, and HDL cholesterol and two distinct trajectories (low and high) of triglycerides were identified. n-PFOS, Sm-PFOS, and PFHxS were positively associated with total and LDL cholesterol trajectories. n-PFOS was inversely associated with triglycerides trajectories. PFAS mixtures (high vs. low) showed positive associations with total and LDL cholesterol trajectories (high vs. low), showing ORs (95% CIs) of 1.69 (95% CI: 1.36, 2.12) and 1.79 (95% CI: 1.44, 2.22), respectively. Discussion: Concentrations of serum PFAS were positively associated with trajectories of total and LDL cholesterol, providing a line of evidence supporting adverse effects of PFAS on lipid homeostasis. https://doi.org/10.1289/EHP12351
Reconstruction of the last bacterial common ancestor from 183 pangenomes reveals a versatile ancient core genome
Authors: Jason C. Hyun, Bernhard O. Palsson
Journal: Genome biology (2023)

Cumulative sequencing efforts have yielded enough genomes to construct pangenomes for dozens of bacterial species and elucidate intraspecies gene conservation. Given the diversity of organisms for which this is achievable, similar analyses for ancestral species are feasible through the integration of pangenomics and phylogenetics, promising deeper insights into the nature of ancient life.We construct pangenomes for 183 bacterial species from 54,085 genomes and identify their core genomes using a novel statistical model to estimate genome-specific error rates and underlying gene frequencies. The core genomes are then integrated into a phylogenetic tree to reconstruct the core genome of the last bacterial common ancestor (LBCA), yielding three main results: First, the gene content of modern and ancestral core genomes are diverse at the level of individual genes but are similarly distributed by functional category and share several poorly characterized genes. Second, the LBCA core genome is distinct from any individual modern core genome but has many fundamental biological systems intact, especially those involving translation machinery and biosynthetic pathways to all major nucleotides and amino acids. Third, despite this metabolic versatility, the LBCA core genome likely requires additional non-core genes for viability, based on comparisons with the minimal organism, JCVI-Syn3A.These results suggest that many cellular systems commonly conserved in modern bacteria were not just present in ancient bacteria but were nearly immutable with respect to short-term intraspecies variation. Extending this analysis to other domains of life will likely provide similar insights into more distant ancestral species.
A half-century of research on tuberculosis: Successes and challenges
Authors: Barry R. Bloom
Journal: The Journal of Experimental Medicine (2023)

Great progress has been made over the past half-century, but TB remains a formidable global health problem, particularly in low- and middle-income countries. Understanding the mechanisms of pathogenesis and necessary and sufficient conditions for protection are critical. The need for inexpensive and sensitive point-of-care diagnostic tests for earlier detection of infection and disease, shorter and less-toxic drug regimens for drug-sensitive and -resistant TB, and a more effective vaccine than BCG is immense. New and better tools, greater support for international research, collaborations, and training will be required to dramatically reduce the burden of this devastating disease which still kills 1.6 million people annually.
An oncolytic virus–delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment
Authors: Kristin DePeaux, Dayana B. Rivadeneira, Konstantinos Lontos, Victoria G. Dean, William G. Gunn, McLane J. Watson, Tianhong Yao, Drew Wilfahrt, Cynthia Hinck, Lukasz Wieteska, Stephen H. Thorne, Andrew P. Hinck, Greg M. Delgoffe
Journal: The Journal of Experimental Medicine (2023)

While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFNγ, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFβ, which blunted IFNγ signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFβRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFβ inhibition had no toxicities associated with systemic TGFβ/TGFβR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer.
NET histones inflame periodontitis
Authors: Venizelos Papayannopoulos
Journal: The Journal of Experimental Medicine (2023)

Microbial dysbiosis triggers inflammatory periodontitis. In this issue of JEM, Kim et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20221751) demonstrate that neutrophil extracellular trap histones are the major mediators fueling the pathogenic Th17 inflammation that promotes gum and bone loss in periodontitis.
How to: a practical guide to cardiac conduction devices on chest radiograph
Authors: Kyaw Soe Tun, Donnchadh Reidy, Una Buckley
Journal:  (2023)

Abstract With the increasing number of cardiac conduction devices (CCDs) insertions with various complexities in recent decades, it is crucial for clinicians (especially internal medicine residents and cardiologists) to have an up-to-date review of the current devices on chest radiograph. Chest X-ray remains the most cost-effective and accessible imaging modality to assess the device position and its associated complications, not only immediately after insertion but also during the follow-up visit as outpatient. Various types of CCDs such as permanent pacemaker, implantable cardioverter defibrillator, and cardiac resynchronization therapy (CRT, CRT with defibrillation or pacing) with their appearances on chest radiograph and possible complications with a step-by-step guide to how to assess are discussed in this article.